| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or metastatic PD-L1-positive squamous cell carcinoma of the head and neck (SCCHN). |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of MEDI4736 monotherapy in terms of objective response rate (ORR). |
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| E.2.2 | Secondary objectives of the trial |
To further assess the efficacy of MEDI4736 monotherapy in terms of objective response rate (ORR), duration of response (DoR), disease control rate (DCR), deep sustained response (DSR), progression-free survival (PFS), and overall survival (OS).
To explore symptoms and health-related quality of life (QoL) in patients treated with MEDI4736 monotherapy using the EORTC 30-item core quality of life questionnaire, version 3 (QLQ-C30 v3) and the 35-item head and neck quality of life questionnaire (QLQ-H&N35) module.
To assess the safety and tolerability profile of MEDI4736 monotherapy |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
AstraZeneca intends to perform genetic research in the MEDI4736 clinical development program to explore how genetic variations may affect the clinical parameters associated with this drug. Collection of DNA samples from populations with well-described clinical characteristics may lead to improvements in the design and interpretation of clinical trials and, possibly, to genetically guided treatment strategies.
The objective of this research is to collect and store DNA, derived from a blood sample, for
future exploratory research into genes/genetic variations that may influence response, ie,
distribution, safety, tolerability, and efficacy of MEDI4736, and/or susceptibility to SCCHN.
All enrolled patients who take part in the main study will be asked to participate in this genetic
research. Participation is voluntary. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described in the main body of the Clinical Study Protocol and provide informed consent for the genetic sampling and analyses.
Blood samples will ideally be collected during the screening/baseline period. If for any reason
the sample is not drawn during the screening/baseline period, it should be taken as soon as
possible, but not later than the last study visit. Only 1 sample should be collected per patient for genetics during the study. |
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| E.3 | Principal inclusion criteria |
1. Age ≥18 years at the time of screening
2. Written informed consent and any locally required authorization obtained from the patient/legal
representative prior to performing any protocol-related procedures, including screening evaluations
3. Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Patients who refuse radical resection are eligible.
4. Tumor progression or recurrence during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease that must have contained a platinum agent. Patient who have only received chemo-radioation with curative intent for treatment of their locally advanced disease or recurrent diesease are not eligible.
5. Able and willing to give valid written consent to provide newly acquired tumor tissue (preferred) or archival tissue (< 3 years) for the purpose of establishing PD-L1 status. Tumor lesions used for newly acquired biopsies should not be the same lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.
6. Confirmed PD-L1–positive SCCHN by the Ventana SP263 assay on newly acquired tumor tissue (preferred) or archival tissue (< 3 years old). If the patient's PD-L1 has already been assessed using the analytically validated Ventana assay as a part of the screening process for another AstraZeneca/Medimmune study, this test result can be used for the determination of eligibility.
7. WHO/ECOG performance status of 0 or 1 at enrollment.
8. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions in a previously irradiated field can be used as measurable disease provided that there has been demonstrated progression in the lesion.
9. Patients must have no prior exposure to immune-mediated therapy, including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.Prior exposure to other investigational agenty may be permitted after discussion with the sponsor.
10. Adequate organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening, defined as:
- Hemoglobin ≥9 g/dL
- Absolute neutrophil count ≥1500/mm3
- Platelet count ≥100000/mm3
- Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
- ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
- Calculated creatinine clearance ≥40 mL/min as determined by Cockcroft-Gault (using actual body weight)
11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and folliclestimulating hormone levels in the post-menopausal range for the institution.
- Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral ophorectomy or hysterectomy). |
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| E.4 | Principal exclusion criteria |
1. Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck (eg, paranasal cavity), patients with squamous cell carcinoma of the head and neck of unknown primary, and non-squamous histologies (eg, nasopharynx or salivary gland).
2. Received more than 1 systemic palliative regimen for recurrent or metastatic disease.
3. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
4. Prior randomization or treatment in a previous MEDI4736 and / or tremelimumab clinical study regardless of treatment arm assignment or receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
5. Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of study treatment. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Investigator.
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criterion
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with MEDI4736 (eg, hearing loss) may be included after consultation with the Study Physician.
8. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre-medication)
9. History of allogeneic organ transplantation
10. Active or prior documented autoimmune or inflammatory disorders (eg, inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or other chronic skin conditions not requiring systemic treatment
11. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs from MEDI4736 , or compromise the ability of the patient to give written informed consent
12. History of another primary malignancy except for *Malignancy
treated with curative intent and with no known active disease ≥5 years
before the first dose of study drug and of low potential risk for recurrence *Adequately treated non-melanoma skin cancer or lentigo
maligna without evidence of disease *Adequately treated carcinoma in
situ without evidence of disease eg cervical cancer in situ
13. Patients with history of brain metastases, spinal cord compression, a history of leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs
14. History of active primary immunodeficiency
15. Known history of previous clinical diagnosis of tuberculosis
16. Active infection including hep B, hep C, or HIV
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17. Receipt of live, attenuated vaccine within 30 days prior to the first dose of MEDI4736.
18. Female patients who are pregnant or breast-feeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of MEDI4736
19. Known allergy or hypersensitivity to MEDI4736 or any excipient
20. Mean QT interval corrected for heart rate ≥470 msec calculated from 3 ECGs using Fridericia's Correction;
21. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the objective response rate (ORR). ORR is defined as the number (%) of patients with a confirmed overall response of complete response (CR) or partial response (PR) and will be based on all treated patients who have measurable disease at baseline per BICR. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A confirmed response of confirmed or partial response means that a response of complete or partial response is recorded at one visit and confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and confirmed or partial response confirmation visit. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of objective response rate. |
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| E.5.2 | Secondary end point(s) |
1. Duration of response (DoR) - time from the date of first documented response until the first date of documented progression or death in the absence of disease progression.
2. Disease control rate (DCR) - percentage of patients who have a best objective response (BoR) of confirmed or partial response in the first 4 or 12 months or who have demonstrated stable disease (SD) for a minimum interval of 16 or 52 weeks following the start of treatment.
3. Deep sustained response (DSR) - the percent of patients with a 30% decrease in the sum of target lesions that has been sustained for 12 months or a 50% decrease in the sum of target lesions that has been sustained for 6 months.
4. Progression-free survival (PFS) - time from the date of first dose until the date of objective disease progression or death.
5. Overall survival (OS) - time from the date of enrollment until death due to any cause.
6. Best objective response (BoR) - the best response a patient has had during their time in the
study up until RECIST or confirmed progression or the last evaluable assessment. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. DoR - time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR.
2. DCR - first 4 or first 12 months.
3. DSR - 12 months for 30% decrease and 6 months for 50% decrease.
4. PFS time will be derived based on scan/assessment dates.
5. OS - Survival calls will be made in the week following the date of data cut-off for the analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off date, these patients will be censored at the date of data cut-off.
6. BoR - for deaths occuring ≤17 weeks after enrollment BoR will be assigned to the progressive disease (PD) category and for deaths occuring >17 weeks after enrollment BoR will be assigned to the not evaluable (NE) category.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Georgia |
| Germany |
| Hungary |
| Israel |
| Korea, Republic of |
| Malaysia |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last patient undergoing the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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